Hepatocellular Carcinoma: Targeted Therapy and Multidisciplinary P17 pps

With the probe positioned on the liver surface the surgeon’s fingertip pushes on the opposite side and its profile is visualized at IOUS: as a consequence the relation between the finger

this maneuver the flat and thin tip of the electrocautery is positioned between the probe and the liver surface: this maneuver results in a shadow at the IOUS image which runs deeply just below the electrocautery In this way it is possible to define the position of the electrocautery with the tumor edge and consequently to mark with the electrocautery itself the nodule profile on the liver surface and select the safer edge for the incision Furthermore, the adequacy of the marked edge can be checked with IOUS as the air trapped between the probe and the irregular surface

of the demarcation line drawn with the electrocautery on the liver surface can be visualized at IOUS

Another way to draw precisely on the liver surface with the aid of IOUS the tumor edge is carried out using the fingertips With the probe positioned on the liver surface the surgeon’s fingertip pushes on the opposite side and its profile is visualized at IOUS: as a consequence the relation between the fingertip and the tumor edge can

be precisely estimated and the resection area can be marked on the liver surface The main target to be obtained once the resection area is drawn on the liver surface is that of achieving at the end of the dissection the flattest and most regular cut surface

Liver Parenchyma Dissection

The main advantage provided by the resection guidance accomplished with the aid

of IOUS is the modification of the traditional way to dissect the liver tissue, which was done on vertical planes to avoid tumor exposure on the cut surface IOUS allows

to follow in real-time the dissection plane, to put it constantly in relation to the tumor edge, and then to modify its direction when needed This is because it is possible

to visualize on the IOUS image the dissection plane which appears as an echogenic line due to the entrapment of air bubbles and clots between the faced cut surfaces (Fig.10.7) If the dissection plane is not clearly visible, it can be better visualized inserting a gauze or a specifically devised silicon gauze between the faced cut sur-faces These techniques allow the surgeon to keep the proper dissection plane: an early recognition of a wrong dissection plane permits to modify it properly, and to avoid a possible tumor exposure In this way it is possible to carry out a rounded tra-jectory of the dissection plane around the tumor avoiding its exposure, and allowing

to spare important vascular structures; this results in more conservative but radical treatments and in a lower rate of major hepatectomies

The artifacts which allow to show the dissection plan at IOUS could some-times mask structures such as portal branches that should be ligated or conversely respected For this reason, to better visualize the targeted point where the portal branch should be divided, the so-called hooking technique has been devised [30] When the Glissonian sheath is exposed and skeletonized, it is encircled with a stitch, which is visualized by IOUS as an echogenic spot with a posterior shadow Then under sonographic control, the stitch, hooking the exposed vessel, is gently pulled

up, which stretches the portal branch slightly and the traction point is shown clearly

by IOUS If the exposed portal branch is not clearly visible because it has collapsed, the portal triad is unclamped to enable it to fill with blood and then it is better

146 G Torzilli

Fig 10.7 The dissection line

(DL) can be well visualized

(arrows) at IOUS, and it runs

towards the tumor (T)

visualized by IOUS If the target site is correct, the portal branch is ligated and divided and segmentectomy is completed under IOUS guidance; conversely, if the exposed vessel was not the targeted one, it is spared and useless sacrifice of further liver parenchyma is avoided

A practical example in which the hooking technique is used is during ventral or dorsal subsegmentectomy of segment 8 The portal trunk to this segment may show bifurcation in its dorsal branch and ventral trunk just close to the origin of the portal vessel to segment 5 In this situation, there is the risk of ligating and dividing the portal branch of segment 5 instead of the planned subsegmental branch of segment

8 and then, necrosis of segment 5 may occur The hooking technique under IOUS control enables the identification of the branch, which was encircled, and then the surgeon can decide with certainty whether to ligate it This technique is also useful

in the case of tumor thrombus in major portal branches In this situation, once the portal branch is skeletonized, it is encircled with a stitch and, under IOUS control, the stitch is gently pulled up; this traction stretches the portal branch slightly and the traction point is shown clearly by IOUS (Fig.10.8) If the traction point is not at the level of the tumor thrombus it is possible to ligate the portal branch and proceed with the liver resection being sure that the thrombus will not migrate because of surgical manipulation

During liver dissection the backflow bleeding from the hepatic veins is an impor-tant source of blood loss, and it is one of the most imporimpor-tant factors in determining the short- and long-term outcome for the patient Therefore, limiting the backflow bleeding from the hepatic veins is a priority in liver resections An ultrasound-guided technique for backflow bleeding control from the right hepatic vein (RHV)

Fig 10.8 On the left, the portal branch to segments 5 and 8 (P5–8) is occupied by a tumor

throm-bus (TT) approaching its origin; at this level P5–8 is encircled On the right, traction is applied

(arrows) pulling up the stitch and at IOUS the level of the traction does not involve the tumor

thrombus; therefore, P5–8 can be safely ligated at that level P6–7: portal branch to segments

6 and 7

during right-sided liver resection has been recently described [37] The technique

is very simple and is now applied to every hepatic vein Once the hepatocaval confluence is exposed anteriorly, dissection proceeds until the right surface of the extrahepatic RHV is exposed in case the RHV has to be controlled, the left surface

of the extrahepatic left hepatic vein (LHV) for the LHV itself, and the right-anterior surface of the middle hepatic vein (MHV) for the MHV itself The surgeon’s fin-gertips compress the vessel at the exposed side, and the effectiveness of finger compression is checked by IOUS, and color-Doppler

Postresectional Control

There are two possibilities given by IOUS after nodule removal: one is the “water bath” technique which consists in the real-time control of the proper resection of the targeted nodule verifying its complete inclusion in the specimen just removed from the liver [38]; the second is done checking the cut surface refilled with saline

to avoid the artifacts generated by the residual air bubbles and clots

Major Hepatectomy

In those patients in which major resections are needed with removal of at least three adjacent segments, IOUS allows us to better achieve the proper dissection plane, which should run along the hepatic vein to be fully anatomic Color-Doppler is a useful aid in these patients because it helps verify the preserved vascular supply of

148 G Torzilli the liver to be spared, before ligation of the vessels skeletonized at the hepatic hilum Furthermore, color-Doppler IOUS allows the proper positioning of the remaining liver till the in- and outflow are proper in terms of velocity and waveform [39]

Conclusions

IOUS still remains the best method for staging liver involvement by the tumor, and

it has been discussed how new improvements are expected by adding the CEIOUS with the aim of ameliorating the specificity of ultrasound exploration IOUS is cer-tainly the best method for the surgeon to understand the liver anatomy and the relations between tumors and intrahepatic vessels This information is crucial for planning the resection and in this sense IOUS probably has the most important role guiding the surgeon’s hand in real-time during the liver parenchyma dissection The aforementioned methods for performing an IOUS-guided resection guarantee when-ever possible both anatomical and limited resection with a radical intent: this has consequences for the effectiveness of the surgical treatment as well as for its safety Indeed, this kind of surgery allows radical surgical treatment of HCC without mor-tality Procedures that are not IOUS-guided lead to dangerous and useless major resection or incomplete operations Inversely, IOUS tumor-vessel classification and the related surgical policy have proven that in selected patients it is possible to get close to the tumor burden without increasing the risk of incomplete removal and, consequently, of local recurrence [5,6] In practice this evidence means that with IOUS guidance it is possible to perform conservative but radical hepatectomies also

in complex presentations, and then to enlarge the surgical indications With this approach the rate of major hepatectomies has been limited to up to 8% in patients with tumors involving one or more hepatic veins close to their caval confluence, without performing any vascular reconstruction [6] These results not only under-line how IOUS guidance allows otherwise infeasible operations but, just because this approach reduces the rate of major hepatectomies, there can be discussion of the real need for interventions such as preoperative portal vein embolization which are adopted to secure the patient from liver failure after major removal of liver parenchyma

Nowadays, it can be affirmed that liver resection is an imaging-guided proce-dure and as with every interventional imaging-guided proceproce-dure, its features are the highest therapeutic efficacy combined with minimal invasiveness With IOUS aid it

is nowadays possible to carry out surgical procedures comparatively safely, onco-logically radical, and conservative for the liver function Mostly because of that, surgery can still be considered the treatment of choice for most liver tumors For this purpose, IOUS should be a familiar instrument for hepatic surgeons The American College of Surgeons has recently recognized the need for surgeons with specific training in US, and similarly a School for Surgical Ultrasonography has been started

in Europe; meanwhile dedicated monographs have been published almost simul-taneously in America and in Europe [40, 41] The way for a wider diffusion of ultrasound in the surgeon’s practice has been definitely opened

1 Liu CL, Fan ST, Lo CM, Wong Y, Ng IO, Lam CM, Poon RT, Wong J (2004) Abdominal drainage after hepatic resection is contraindicated in patients with chronic liver diseases Ann Surg 239:194–201

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3 Bruix J, Sherman M (2005) Practice Guidelines Committee, American Association for the Study of Liver Diseases Management of hepatocellular carcinoma Hepatology 42: 1208–1236

4 Makuuchi M, Yamazaki S, Hasegawa H et al (1980) Ultrasonically guided liver surgery Jpn

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5 Torzilli G, Montorsi M, Donadon M et al (2005) “Radical but conservative” is the main goal for ultrasonography-guided liver resection: prospective validation of this approach J Am Coll Surg 201:517–528

6 Torzilli G, Montorsi M, Del Fabbro D, Palmisano A, Donadon M, Makuuchi M (2006) Ultrasonographically guided surgical approach to liver tumors involving the hepatic veins close to the caval confluence Br J Surg 93:1238–246

7 Torzilli G, Palmisano A, Del Fabbro D et al (2007) Contrast-enhanced intraoperative ultra-sonography during surgery for hepatocellular carcinoma in liver cirrhosis: is it useful or useless? A prospective cohort study of our experience Ann Surg Oncol 14:1347–1355

8 Torzilli G, Del Fabbro D, Olivari N, Calliada F, Montorsi M, Makuuchi M (2004) Contrast-enhanced ultrasonography during liver surgery Br J Surg 91:1165–1167

9 Terminology Committee of the International Hepato-Pancreato-Biliary Association (2000) The Brisbane 2000 Terminology of Liver Anatomy and Resections HPB 2:333–339

10 Kokudo N, Bandai Y, Imanishi H et al (1996) Management of new hepatic nodules detected by intraoperative ultrasonography during hepatic resection for hepatocellular carcinoma Surgery 119:634–640

11 Takigawa Y, Sugawara Y, Yamamoto J et al (2001) New lesions detected by intraopera-tive ultrasound during liver resection for hepatocellular carcinoma Ultrasound Med Biol 27: 151–156

12 Roncalli M, Roz E, Coggi G et al (1999) The vascular profile of regenerative and dysplas-tic nodules of the cirrhodysplas-tic liver: implications for diagnosis and classification Hepatology 30:1174–1178

13 Quaia E, Calliada F, Bertolotto M et al (2004) Characterization of focal liver lesions with contrast-specific US modes and a sulfur hexafluoride-filled microbubble contrast agent: diagnostic performance and confidence Radiology 232:420–430

14 Takada T, Yasuda H, Uchiyama K, Hasegawa H, Shikata J (1990) Contrast-enhanced intraoperative ultrasonography of small hepatocellular carcinoma Surgery 107: 528–532

15 Kojiro M (2004) Focus on dysplastic nodules and early hepatocellular carcinoma: an Eastern point of view Liver Transpl 10(2 Suppl 1):3–8

16 Hatanaka K, Kudo M, Minami Y et al (2008) Differential diagnosis of hepatic tumors: value of contrast-enhanced harmonic sonography using the newly developed contrast agent, Sonazoid Intervirology 51(Suppl 1):61–69

17 Jarnagin WR, Bach AM, Winston CB et al (2001) What is the yield of intraoperative ultrasonography during partial hepatectomy for malignant disease? J Am Coll Surg 192: 577–583

18 Cerwenka H, Raith J, Bacher H et al (2003) Is intraoperative ultrasonography dur-ing partial hepatectomy still necessary in the age of magnetic resonance imagdur-ing? Hepatogastroenterology 50:1539–1541

19 Torzilli G, Donadon M, Marconi M et al (2008) Systematic extended right posterior sectionectomy: a safe and effective alternative to right hepatectomy Ann Surg 247:603–611

150 G Torzilli

20 Torzilli G, Palmisano A, Procopio F, Botea F, Del Fabbro D, Montorsi M (2010) A new systematic small for size resection for liver tumors invading the middle hepatic vein at its caval confluence: the mini-mesohepatectomy Ann Surg 251:33–39

21 Hasegawa K, Kokudo N, Imamura H et al (2005) Prognostic impact of anatomic resection for hepatocellular carcinoma Ann Surg 242:252–259

22 Torzilli G, Makuuchi M (2004) Ultrasound-guided finger compression in liver subsegmentec-tomy for hepatocellular carcinoma Surg Endosc 18:136–139

23 Torzilli G, Procopio F, Cimino M, Del Fabbro D, Palmisano A, Donadon M, Montorsi

M (2010) Anatomical segmental and subsegmental resection of the liver for hepatocellular carcinoma: a new approach by means of ultrasound-guided vessel compression Ann Surg 251:229–235

24 Torzilli G, Procopio F, Palmisano A, Cimino M, Del Fabbro D, Donadon M, Montorsi M (2009) New technique for defining the right anterior section intraoperatively using ultrasound-guided finger counter-compression J Am Coll Surg 209(2):e8–11

25 Takayama T, Makuuchi M, Watanabe K, Kosuge T, Takayasu K, Yamazaki S, Hasegawa

H (1991) A new method for mapping hepatic subsegment: counterstaining identification technique Surgery 109:226–229

26 Takasaki K, Kobayashi S, Tanaka S, Saito A, Yamamoto M, Hanyu F (1990) Highly anatom-ically systematized hepatic resection with Glissonean sheath code transection at the hepatic hilus Int Surg 75:73–77

27 Launois B, Jamieson GG (1992) The posterior intrahepatic approach for hepatectomy or removal of segments of the liver Surg Gynec Obstet 174:155–158

28 Strasberg S, Linehan DC, Hawkins WG (2008) Isolation of right main and right sectional portal pedicles for liver resection without hepatotomy or inflow occlusion J Am Coll Surg 206:390–396

29 Onishi H, Kawarada Y, Das BC et al (2000) Surgical anatomy of the medial segment (S4)

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30 Torzilli G, Takayama T, Hui AM, Kubota K, Harihara Y, Makuuchi M (1999) A new technical aspect of ultrasound-guided liver surgery Am J Surg 178:341–343

31 Kaibori M, Matsui Y, Hijikawa T, Uchida Y, Kwon AH, Kamiyama Y (2006) Comparison of limited and anatomic hepatic resection for hepatocellular carcinoma with hepatitis C Surgery, 139(3):385–394

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Portal Vein Embolization Prior to Resection

David C Madoff and Rony Avritscher

Keywords Portal vein embolization · Hepatic resection · Liver

regenera-tion· Preoperative PVE · Indications and contraindications for PVE · FLR volume

With improvements in perioperative care, major hepatic resections are increas-ingly being performed for primary and metastatic hepatobiliary neoplasia Although fatal hepatic failure and major technical complications are now rare after resection, impaired synthetic function, fluid retention, and cholestasis still contribute to pro-longed recovery time and extended hospital stay [1,2] Although there are many potential contributing causes for perioperative hepatic failure, volume of the future liver remnant (FLR) constitutes one of the most important risk factors Patients con-sidered at “high risk” for perioperative failure are those with chronic liver disease

in whom more than 60% of the functional liver mass will be removed or those with normal underlying liver who undergo resection of more than 80% of their functional liver mass [2 5]

Preoperative portal vein embolization (PVE) is a procedure used to reduce the risk of extensive surgery in patients with small remnant livers [5 15] PVE redirects portal blood flow to the intended future liver remnant in an attempt to initiate hyper-trophy of the non-embolized segments and has been shown to improve the functional reserve of the FLR before surgery In appropriately selected patients, PVE has also been shown to reduce perioperative morbidity and allow for safe, potentially cura-tive hepatectomy for patients previously considered ineligible for resection based on anticipated small remnant livers [5 16] For this reason, PVE is now performed at many comprehensive hepatobiliary centers worldwide prior to major hepatectomy The clinical use of PVE is based on laboratory investigations first reported by Rous and Larimore [17] in 1920 In their experiments, Rous and Larimore observed the effects of segmental portal venous occlusion in rabbits and found hypertrophy (i.e., enlargement) of the hepatic segments with patent portal veins and atrophy

D.C Madoff (B)

Interventional Radiology Section, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

153

K.M McMasters, J.-N Vauthey (eds.), Hepatocellular Carcinoma,

DOI 10.1007/978-1-60327-522-4_11,  C Springer Science+Business Media, LLC 2011

154 D.C Madoff and R Avritscher (i.e., shrinkage) of the hepatic segments with ligated portal veins Clinical researchers subsequently reported their results showing that portal vein or bile duct occlusion resulting from tumor invasion or ligation leads to atrophy of the liver

to be resected (i.e., ipsilateral liver) and hypertrophy of liver to remain in situ after resection (i.e., contralateral liver) [18–20] In the 1980s, Kinoshita and col-leagues [21] first described the use of PVE to limit the extension of segmental portal tumor thrombi from hepatocellular carcinoma (HCC) for which transcatheter arte-rial embolization (TAE) was ineffective In 1990, Makuuchi and colleagues [10] were first to report on the use of PVE solely as a method to prepare the contralateral liver for major hepatectomy in 14 patients with hilar biliary tract cancer

Since publication of these seminal articles, many investigators have stressed the importance of PVE in their multidisciplinary management of patients with HCC, cholangiocarcinoma, and liver metastases Given this, extensive research efforts into the mechanisms of liver regeneration, indications and contraindications for PVE, methods of measuring the FLR before and after PVE, technical aspects of PVE, and potential surgical strategies are ongoing and in continual evolution This chap-ter reviews the current indications for and technical aspects of PVE before hepatic resection, with an emphasis on strategies to improve outcomes

Mechanisms of Liver Regeneration

The liver’s ability to regenerate after injury or resection has long been known with

the earliest reference being from classical Greek literature, in Hesiod’s Theogony

(750–700 B.C.) [22] However, the human liver’s regenerative capacity was not scientifically documented until 1890 [23]

Despite its sizeable metabolic burden, the liver is basically an inactive organ

in terms of hepatocyte replication, with only 0.0012–0.01% of hepatocytes under-going mitosis at any time [22, 24, 25] However, this low rate of cell turnover

in healthy liver can be altered by substantial toxic damage or surgical resection, which stimulates sudden, massive hepatocyte proliferation resulting in recovery of the functional liver mass within 2 weeks after the loss of up to two-thirds of the liver This regenerative response is usually mediated by the proliferation of surviv-ing hepatocytes within the acinar architecture of the remnant liver After resection, this response results in hypertrophy of the remnant liver rather than restoration of the resected segments, a phenomenon that is appropriately termed “compensatory hyperplasia” rather than true “regeneration” [25] The term “hypertrophy” actu-ally means an increase in cell size and may be misleading because the primary mechanism of volume restitution after liver resection or embolization is more pre-cisely termed “hyperplasia,” or increase in cell number [26–28] However, studies also suggest that both hypertrophy and hyperplasia aid in restoring functional hep-atic volume [29–31] Thus, the term “hypertrophy” after PVE or resection will be used throughout this chapter since this is the term used throughout the published literature